Tumor Microenvironment-Based Biomarkers in African American Prostate Cancer
Abstract
African American (AA) men have a higher incidence and significantly higher mortality rate from prostate cancer (PCa) than European American (EA) men. Unfortunately, in the vast majority of PCa molecular genetic studies, there is a general underrepresentation of AA men. In this application we will take advantage of our extensive AA PCa tissue resources to address the biological causes of the disparity in PCa mortality in AA men compared to EA men. The central problem addressed in this proposal is to understand the biological basis for the more aggressive clinical behavior of PCa in AA men, to develop predictive tools to help manage PCa in AA men, and to identify novel therapeutic targets in AA men. It is known that the tumor microenvironment (the tissue around the cancer cells in a tumor mass) interacts with cancer cells, and cancer cells impact the surrounding tissues as well. The tissue surrounding the cancer cells is called reactive stroma (since it is reacting to the cancer cells). We have shown previously that PCas with more abundant reactive stroma have more aggressive clinical behavior. In addition, we have shown that reactive stroma is associated with changes in gene expression in the stroma, and these genes can increase cancer growth in mouse models when expressed in stroma. These studies have been carried out in EA PCa cohorts. Our new pilot studies show that abundant reactive stroma is much more common in AA PCa than EA PCa. Since abundant reactive stroma is associated with aggressive clinical behavior, this may account for some of the increased aggressiveness seen in AA PCa (relative to EA PCa). In addition, we have shown increased expression of multiple stromal genes in AA PCa that are not increased in EA PCa. Our hypothesis is that stromal biomarkers will improve our ability to predict outcome in AA men with PCa. Our goal is to test whether a quantitative test that measures the amount of reactive stroma by image analysis and/or quantitation of specific stromal markers will reveal predictive biomarkers of disease outcome. We hypothesize that such biomarkers will improve prediction of outcomes over currently used algorithms in the AA population. The goal is to be able to more accurately identify those patients who can benefit from combined modality treatments or adjuvant/neoadjuvant approaches or more intense follow-up after radical prostatectomy. The ability to identify these patients early would represent an important advancement. It should be noted that, while we are focused on developing such markers for AA men, they may also be useful in a subset of EA men. Currently many men, including AA men, are overtreated for clinically localized PCa. New tools for stratifying patients for active surveillance versus immediate definitive treatment are desperately needed. While the proposed studies will be carried out in tissue microarrays, they can be translated into biopsy-based assays if they show strong independent predictive power. We have available large numbers of biopsies from AA men that could be deployed in future studies of stromal biomarkers as selection criteria for AA men to undergo active surveillance. Finally, our approach may identify novel microenvironment-based therapeutic targets. Identification of altered expression, evaluation of biological relevance, and correlation with treatment outcome for specific stromal proteins will allow us to rationally stratify such potential targets. Since the specific stromal proteins we are studying are at least partially outside the cell, they can be readily targeted by antibody or immune-based therapy. Another advantage of stromal targets is that they are produced by stromal cells, which are far less genetically variable and plastic than tumor cells. As such, therapeutic resistance is less likely to occur via mutation or other genetic alterations, since they are derived from normal tissue cells. We suggest that our approach will ultimate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810462
Entities
People
- Michael M. Ittmann
Organizations
- Baylor College of Medicine
- United States Army